The present invention provides novel compounds, novel compositions and methods for their use and manufacture. The compounds and compositions of the present invention are generally useful pharmacologically as therapeutic agents in disease states alleviated by the inhibition or antagonism of protein kinase activated signalling pathways in general, and in particular in the pathological processes which involve aberrant cellular proliferation, such disease states including tumor growth, restenosis, atherosclerosis, and thrombosis. In particular, the present invention relates to a series of substituted aza-oxindole compounds, which exhibit protein tyrosine kinase and protein serine/threonine kinase inhibition, and which are useful for the prevention of chemotherapy-induced alopecia.
Protein kinases play a critical role in the control of cell growth and differentiation and are key mediators of cellular signals leading to the production of growth factors and cytokines. See, for example, Schlessinger and Ullrich, Neuron 1992, 9, 383. A partial, non-limiting, list of such kinases includes abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms, c-kit, c-met, cRaf1, CSF1R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1, IKK2, IKK3, INS-R, Integrin-linkedkinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCxcex1, PKCxcex2, PKCxcex4, PKCxcex5, PKCxcex3, PKCxcex, PKCxcexc, PKCxcex6, PLK1, Polo-like kinase, PYK2, tie1, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70. Protein kinases have been implicated as targets in central nervous system disorders such as Alzheimer""s (Mandelkow, E. M. et al. FEBS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167,99), pain sensation (Yashpal, K. J. Neurosci. 1995, 15, 3263-72), inflammatory disorders such as arthritis (Badger, J. Pharm. Exp. Ther. 1996, 279, 1453), psoriasis (Dvir, et al, J. Cell Biol. 1991, 113, 857), bone diseases such as osteoporosis (Tanaka et al, Nature, 1996, 383, 528), cancer (Hunter and Pines, Cell 1994, 79, 573), atherosclerosis (Hajjar and Pomerantz, FASEB J. 1992, 6, 2933), thrombosis (Salari, FEBS 1990, 263, 104), metabolic disorders such as diabetes (Borthwick, A. C. et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), blood vessel proliferative disorders such as angiogenesis (Strawn et al Cancer Res. 1996, 56, 3540; Jackson et al J. Pharm. Exp. Ther. 1998, 284, 687), restenosis (Buchdunger et al, Proc, Nat. Acad. Sci USA 1991, 92, 2258), autoimmune diseases and transplant rejection (Bolen and Brugge, Ann. Rev. Immunol. 1997, 15, 371) and infectious diseases such as viral (Littler, E.Nature 1992, 358, 160), and fungal infections (Lum, R. T. PCT Int. Appl., WO 9805335 A1 980212).
The signals mediated by kinases have also been shown to control growth, death and differentiation in the cell by regulating the processes of the cell cycle (Massague and Roberts, Current Opinion in Cell Biology 1995, 7, 769-72). Progression through the eukaryotic cell cycle is controlled by a family of kinases called cyclin dependent kinases (CDKs) (Myerson, et al., EMBO Journal 1992, 11, 2909). The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle (Pines, Trends in Biochemical Sciences 1993, 18, 195; Sherr, Cell 1993, 73, 1059). Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase (Matsushime, et al., Molecular and Cellular Biology 1994, 14, 2066; Ohtsubo and Roberts, Science 1993, 259, 1908; Quelle, et al., Genes and Development 1993, 7, 1559; Resnitzky, et al., Molecular and Cellular Biology 1994, 14, 1669). Progression through S-phase requires the activity of cyclin A/CDK2 (Girard, et al., Cell 1991, 67, 1169; Pagano, et al., EMBO Journal 1992, 11, 961; Rosenblatt, et al., Proceedings of the National Academy of Science USA 1992, 89, 2824; Walker and Maller, Nature 1991, 354, 314; Zindy, et al., Biochemical and Biophysical Research Communications 1992, 182, 1144) whereas the activation of cyclin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset of metaphase (Draetta, Trends in Cell Biology 1993, 3, 287; Murray and Kirschner, Nature 1989, 339, 275; Solomon, et al., Molecular Biology of the Cell. 1992, 3, 13; Girard, et al., Cell 1991, 67, 1169; Pagano, et al., EMBO Journal 1992, 11, 961; Rosenblatt, et al., Proceedings of the National Academy of Science USA 1992, 89, 2824; Walker and Maller, Nature 1991, 354, 314; Zindy, et al., Biochemical and Biophysical Research Communications 1992, 182, 1144). It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer (Pines, Current Opinion in Cell Biology 1992, 4, 144; Lees, Current Opinion in Cell Biology 1995, 7, 773; Hunter and Pines, Cell 1994, 79, 573). The selective inhibition of CDKs is therefore an object of the present invention.
In brief summary, the invention comprises compounds of the formula (I): 
wherein X is selected from the group consisting of: N, CH, CCF3, and C(C1-12 aliphatic);
Y is C or N, with the. proviso that when Y is N, R1 is absent, and Z, A and D are each C;
Z is C or N, with the proviso that when Z is N, R2 is absent, and Y, A and D are each C;
A is C or N, with the proviso that when A is N, R3 is absent, and Y, Z and D are each C;
D is C or N, with the proviso that when D is N, then Y, Z and A are each C; with the further proviso that Y, Z, A and D do not simultaneously all represent C;
R1 is selected from the group consisting of: hydrogen, C1-12 aliphatic, thiol, hydroxy, hydroxy-C1-12 aliphatic, Aryl, Aryl-C1-12 aliphatic, R6-Aryl-C1-12 aliphatic, Cyc, Cyc-C1-6 aliphatic, Het, Het-C1-12 aliphatic, C1-12 alkoxy, Aryloxy, amino, C1-12 aliphatic amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxycarbonyl, halogen, cyano, sulfonamide and nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is selected from the group consisting of: hydrogen, C1-12 aliphatic, N-hydroxyimino-C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 aliphatic, C1-12 alkoxycarbonyl, carboxyl C1-12 aliphatic, Aryl, R6-Aryl-oxycarbonyl, R6-oxycarbonyl-Aryl, Het, aminocarbonyl, C1-12 aliphatic-aminocarbonyl, Aryl-C1-12 aliphatic-aminocarbonyl, R6-Aryl-C1-12 aliphatic-aminocarbonyl, Het-C1-12 aliphatic-aminocarbonyl, hydroxy-C1-12 aliphatic-aminocarbonyl, C1-12-alkoxy-C1-12 aliphatic-aminocarbonyl, C1-12 alkoxy-C1-12 aliphatic-amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, halogen, hydroxy, nitro, C1-12 aliphatic-sulfonyl, aminosulfonyl and C1-12 aliphatic-aminosulfonyl, where R6 Aryl and Het are as defined below;
R1 and R2 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by one or more substituents selected from the group consisting of: C1-12 aliphatic, halogen, nitro, cyano, C1-12 alkoxy, carbonyl-C1-12 alkoxy and oxo;
R3 is selected from the group consisting of: hydrogen, C1-12 aliphatic, hydroxy, hydroxy C1-12 aliphatic, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy and halogen, where Aryl and Het are as defined below;
R2 and R3 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by C1-6 aliphatic and/or C1-6 aliphatic-carbonyl;
R4 is selected from the group consisting of: sulfonic acid, C1-12 aliphatic-sulfonyl, sulfonyl-C1-12 aliphatic, C1-12 aliphatic-sulfonyl-C1-6 aliphatic, C1-6 aliphatic-amino, R7-sulfonyl, R7-sulfonyl-C1-12 aliphatic, R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Arylamino, (R8)1-3-Arylsulfonyl, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino, Het-amino, Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino and aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen or R4 and R5 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by one or more substituents selected from the group consisting of: C1-12 aliphatic, oxo and dioxo;
R6 is selected from the group consisting of: C1-12 aliphatic, hydroxy, C1-12 alkoxy and halogen;
R7 is selected from the group consisting of: hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Het-C1-12-aliphatic, Het-C1-12-alkoxy, di-Het-C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic and hydroxyl, where Het and Aryl are as defined below;
R8 is selected from the group consisting of: hydrogen, nitro, cyano, C1-12 alkoxy, halo, carbonyl-C1-12 alkoxy and halo-C1-12 aliphatic;
Aryl is selected from the group consisting of: phenyl, naphthyl, phenanthryl and anthracenyl;
Cyc is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and optionally has one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of: benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, tetrahydrofuran, tetrazine, thidiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole;
and the salts, esters, amides, carbamat s, solvates, polymorphs, hydrates, polymorphs, affinity reagents and/or prodrugs thereof, in either crystalline or amorphous form.
The esters, amides and and carbamates are preferably hydrolyzable and are more preferably biohydrolyzable. The salts are preferably pharmaceutically acceptable salts.
A more preferred genus of compounds. of the present invention includes compounds of formula (I), defined as follows: 
wherein X is selected from the group consisting of: N, CH and C(C1-6 aliphatic);
Y is C or N, with the proviso that when Y is N, R1 is absent, and Z, A and D are each C;
Z is C or N, with the proviso that when Z is N, R2 is absent, and Y, A and D are each C;
A is C or N, with the proviso that when A is N, R3 is absent, and Y, Z and D are each C;
D is C or N, with the proviso that when D is N, then Y, Z and A are C;
with the further proviso that Y, Z, A and D do not simultaneously all represent C;
R1 is selected from the group consisting of: hydrogen, C1-6 aliphatic, hydroxy-C1-6 aliphatic, Aryl-C1-6 aliphatic, R6-Aryl-C1-6 aliphatic, Cyc-C1-6 aliphatic, Het-C1-6 aliphatic, C1-6 alkoxy, Aryloxy, aminocarbonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, C1-6 alkoxycarbonyl, halogen and nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is selected from the group consisting of: hydrogen, C1-6 aliphatic, R7-C1-6 aliphatic, C1-6 alkoxy, hydroxy-C1-6 aliphatic, C1-6 alkoxycarbonyl, carboxyl C1-6 aliphatic, Aryl, R6-Aryl-oxycarbonyl, R6-oxycarbonyl-Aryl, Het, aminocarbonyl, C1-6 aliphatic-aminocarbonyl, Aryl-C1-6 aliphatic-aminocarbonyl, R6-Aryl-C1-6 aliphatic-aminocarbonyl, Het-C1-6 aliphatic-aminocarbonyl, hydroxy-C1-6 aliphatic-aminocarbonyl, C1-6-alkoxy-C1-6 aliphatic-aminocarbonyl, C1-6 alkoxy-C1-6 aliphatic-amino, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, halogen, hydroxy, nitro, sulfo, C1-6 aliphatic-sulfonyl, aminosulfonyl, C1-6 aliphatic-aminosulfonyl and quaternary ammonium, where R6, R7, Aryl and Het are as defined below;
R1 and R2 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by halogen and/or oxo;
R3 is selected from the group consisting of: hydrogen, C1-6 aliphatic, hydroxy, hydroxy C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, C1-6 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy and halogen, where Aryl and Het are as defined below;
R2 and R3 are optionally joined to form a fused ring select d from the group as defined for Het below, and said fused ring is optionally substituted by C1-6 aliphatic or C1-6 aliphatic-carbonyl;
R4 is selected from the group consisting of: sulfonic acid, C1-12 aliphatic-sulfonyl, sulfonyl-C1-12 aliphatic, C1-12 aliphatic-sulfonyl-C1-6 aliphatic, C1-6 aliphatic-amino, R7-sulfonyl, R7-sulfonyl-C1-12 aliphatic, R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Arylamino, (R8)1-3-Arylsulfonyl, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino Het-amino, Het-sulfonyl, Het-aminosulfonyl aminoiminoamino and aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen;
R4 and R5 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by oxo or dioxo;
R6 is selected from the group consisting of: hydrogen, C1-6 aliphatic, hydroxy, C1-6 alkoxy and halogen;
R7 is selected from the group consisting of: hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Het-C1-12-aliphatic, Het-C1-12-alkoxy, di-Het-C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic and hydroxyl, where Het and Aryl are as defined below;
R8 is hydrogen and/or halo-C1-6 aliphatic;
Aryl is phenyl or naphthyl;
Cyc is selected from th group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and optionally has one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of: benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole; and
the salts, esters, amides, carbamates, solvates, polymorphs, hydrates, affinity reagents and/or prodrugs thereof, in either crystalline or amorphous form. The esters, amides and carbamates are preferably hydrolyzable and are more preferably biohydryzeable. The salts are preferably pharmaceutically acceptable salts.
A highly preferred genus of compounds of the present invention includes compounds of formula (I), defined as follows: 
wherein X is selected from the group consisting of: N, CH and CCH3;
Y is C or N, with the proviso that when Y is N, R1 is absent, and Z, A and D are each C;
Z is C or N, with the proviso that when Z is N, R2 is absent, and Y, A and D are each C;
A is C or N, with the proviso that when A is N, R3 is absent, and X, Y and D are each C;
D is C or N, with the proviso that when D is N, then Y, Z and A are each C; with the further proviso that Y, Z, A and D do not simultaneously all represent C;
R1 is selected from the group consisting of: hydrogen, C,1 aliphatic; hydroxy-C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, Aryl-C1-6 aliphatic, R6-Aryl-C1-6 aliphatic, Cyc-C1-6 aliphatic, Het-C1-6 aliphatic, C1-6 alkoxy, Aryloxy, aminocarbonyl, C1-6 alkoxycarbonyl, halogen and nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is selected from the group consisting of: hydrogen, C1-6 aliphatic, N-hydroxyimino-C1-6 aliphatic, C1-6 alkoxy, C1-6 alkoxycarbonyl, Aryl, R6-Aryloxycarbonyl, Het, aminocarbonyl, C1-6 aliphatic aminocarbonyl, Aryl-C1-6 aliphatic aminocarbonyl, R6-Aryl-C1-6 aliphatic aminocarbonyl, Het-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, hydroxy-C1-6 aliphatic aminocarbonyl, C1-6-alkoxy-C1-6 aliphatic aminocarbonyl, C1-6 alkoxy-C1-6 aliphatic amino, halogen, hydroxy, nitro, C1-6 aliphatic sulfonyl, aminosulfonyl and C1-6 aliphatic aminosulfonyl, where R6, Aryl and Het are as defined below;
R1 and R2 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by halogen and/or oxo;
R3 is selected from th group consisting of: hydrogen, C1-6 aliphatic, hydroxy, hydroxy C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl C1-6 alkoxy, Aryloxy, Het and halogen, where Aryl and Het are as defined below;
R2and R3 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by C1-6 alkyl and/or C1-6 alkylcarbonyl;
R4 is selected from the group consisting of: R7-sulfonyl, R7-sulfonyl C1-6-aliphatic, C1-6 aliphatic sulfonyl-C1-6 aliphatic, R7-aminosulfonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, di-C1-6 aliphatic aminosulfonyl-C1-6 aliphatic, R7-aminosulfonyl C1-6 aliphatic, aminosulfonylamino, R7-C1-6 aliphatic. aminosulfonyl-C1-6 aliphatic, Aryl, Het, R7-Aryl-aminosulfonyl, Het-aminosulfonyl and aminoiminoaminosulfonyl, where; R7, R8, Aryl and Het are as defined below;
R5is hydrogen;
R4 and R5 are optionally joined to form a fused ring selected from the group as defined for Het below, and said used ring is optionally substituted by oxo or dioxo;
R6 is selected from the group consisting of: hydroxy, C1-6 alkoxy and halogen;
R7 is selected, from the group consisting of: hydrogen, C1-6 aliphatic, hydroxy C1-6 alkoxy, hydroxy-C1-6 aliphatic, C1-6 aliphatic carbonyl, Aryl-carbonyl, C1-12 alkoxyalkoxyalkoxyalkoxyalkyl, hydroxyl, Aryl, Aryl-C1-6-alkoxy, Aryl-C1-6-aliphatic, Het, Het-C1-6-alkoxy, di-Het-C1-6-alkoxy, Het-C1-6-aliphatic and di-Het-C1-6 aliphatic;
R8 is trifluoromethyl;
Aryl is phenyl;
Cyc is cyclobutyl;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of: benzimidazole, dihydrothiophene, dioxolane, furan, imidazole, morpholine, oxazole, pyridine, pyrrole, pyrrolidine, thiadiazole, thiazole, thiophene, and triazole;
and the salts, esters, amides, carbamates, solvates, polymorphs, hydrates, affinity reagents and/or prodrugs thereof, in either crystalline or amorphous form. The esters, amides and carbamates are preferably hydrolyzable and are more preferably biohydrolyzable. The salts are preferably pharmaceutically acceptable salts.
A preferred group of compounds of the present invention with respect to the substitutions at R4 are compounds of formula (I): 
wherein X is N or CH;
Y is C or N, with the proviso that when Y is N, R1 is absent, and Z, A and D are each C;
Z is C or N, with the proviso that when Z is N, R2 is absent, and Y, A and D are each C;
A is C or N, with the proviso that when A is N, R3 is absent, and Y, Z and D are each C;
D is C or N, with the proviso that when D is N, Y, Z and A are each C;
with th further proviso that Y, Z, A and D do not simultaneously all represent C;
R1 is selected from the group consisting of: hydrogen, C1-12 aliphatic, thiol, hydroxy, hydroxy-C1-12 aliphatic, Aryl, Aryl-C1-12 aliphatic, R6-Aryl-C1-12 aliphatic, Cyc, Cyc-C1-6 aliphatic, Het, Het-C1-12 aliphatic, C1-12 alkoxy, Aryloxy, amino, C1-12 aliphatic amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxycarbonyl, halogen, cyano, sulfonamide and nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is selected from the group consisting of: hydrogen, C1-2 aliphatic, N-hydroxyimino-C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 aliphatic, C1-12 alkoxycarbonyl, carboxyl C1-12 aliphatic, Aryl, R6-Aryl-oxycarbonyl, R6-oxycarbonyl-Aryl, Het, aminocarbonyl, C1-12 aliphatic-aminocarbonyl, Aryl-C1-12 aliphatic-aminocarbonyl, R6-Aryl-C1-12 aliphatic-aminocarbonyl, Het-C1-12 aliphatic-aminocarbonyl, hydroxy-C1-12 aliphatic-aminocarbonyl, C1-12-alkoxy-C1-12 aliphatic-aminocarbonyl, C1-12 alkoxy-C1-12 aliphatic-amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, halogen, hydroxy, nitro, C1-12 aliphatic-sulfonyl, aminosulfonyl and C1-12 aliphatic-aminosulfonyl, where R6, Aryl and Het are as defined below;
R1 and R2 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C1-12 alkoxy, carbonyl-C1-12 alkoxy and oxo;
R3 is selected from the group consisting of: hydrogen, C1-12 aliphatic, hydroxy, hydroxy C1-12 aliphatic, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as defined below;
R2 and R3 are optionally joined to form a fused ring select d from the group as defined for Het below, and said fused ring is optionally substituted by C1-6 aliphatic and/or C1-6 aliphatic-carbonyl;
R4 is selected from the group consisting of: R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino and aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5is hydrogen;
R4 and R5 are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by oxo or dioxo;
R8 is selected from the group consisting of: C1-12 aliphatic, hydroxy, C1-12 alkoxy and halogen;
R7 is selected from the group consisting of: hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Het-C1-12-aliphatic, Het-C1-12-alkoxy, di-Het-C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic and hydroxyl, where Het and Aryl are as defined below;
R8 is selected from the group consisting of: hydrogen, nitro, cyano, C1-12 alkoxy, halo, carbonyl-C1-12 alkoxy and halo-C1-12 aliphatic; and
Aryl is selected from the group consisting of: phenyl, naphthyl, phenanthryl and anthracenyl;
Cyc is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and optionally has one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of: benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole;
and the salts, esters, amides, carbamates, solvates, polymorphs, hydrates, affinity reagents and/or prodrugs thereof, in either crystalline or amorphous form. The esters, amides and carbamates are preferably hydrolyzable and are more preferably biohydrolyzeable. The salts are preferably pharmacetically acceptable salts.
A preferred group of compounds of the present invention with respect to the substitutions at R4 are compounds of formula (I): 
wherein X is CH;
Y is C or N, with the proviso that when Y is N, R1 is absent, and Z, A and D are each C;
Z is C or N, with the proviso that when Z is N, R2 is absent, and Y, A and D are each C;
A is C or N, with the proviso that when A is N, R3 is absent, and Y, Z and D are each C;
D is C or N, with the proviso that when D is N, Y, Z and A are each C; with the further proviso that Y, Z, A and D do not simultaneously all represent C;
R1 is hydrogen;
R2 is selected from the group consisting of: hydrogen, C1-12 alkoxycarbonyl, Aryl, Het and halogen, where Aryl and Het are as defined below;
R3 is hydrogen or halogen;
R4 is selected from the group consisting of: R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7 sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino and aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5is hydrogen;
R4 and R5 are optionally joined to form a fused ring selected from the group as defined for Het below, and said used ring is optionally substituted by oxo or dioxo;
R7 is selected from the group consisting of: hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Het-C1-12-aliphatic, Het-C1-12-alkoxy, di-Het-C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic and hydroxyl, where Het and Aryl are as defined below;
R8 is selected from the group consisting of: hydrogen, nitro, cyano, C1-12 alkoxy, halo, carbonyl-C1-12 alkoxy and halo-C1-12 aliphatic;
Aryl is selected from the group consisting of: phenyl, naphthyl, phenanthryl and anthracenyl;
Cyc is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and optionally has one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of: benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole;
and the salts, esters, amides, carbamates solvates, polymorphs, hydrates, affinity reagents and/or prodrugs thereof, in either crystalline or amorphous form. The esters, amides and carbamates are preferably hydrolyzable and are more preferably biohydrolyzable. The salts are preferably pharmaceutically acceptable salts.
Due to the presence of an oxindole exocyclic double bond, also included in the compounds of the invention are their respective pure E and Z geometric isomers as well as mixtures of E and Z isomers. The invention as described and claimed does not set any limiting ratios on prevalence of Z to E isomers. Thus, for example, compound number 1 in the tables below is disclosed and claimed as the E geometric isomer thereof, the Z geometric isomer thereof, and a mixture of the E and Z geometric isomers thereof, but not limited by any given ratio(s).
Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula.
Certain of the compounds as described will contain one or more chiral, or asymmetric, centers and will therefore be capable of existing as optical isomers that are either dextrorotatory or levorotatory. Also included in the compounds of the invention are the respective dextrorotatory or levorotatory pure preparations, and mixtures thereof.
Certain compounds of formula (I) above may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula, and these are also included within the scope of the present invention.
The present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof (hereafter identified as the xe2x80x9cactive compoundsxe2x80x9d) for use in medical therapy, and particularly in the treatment of disorders mediated by CDK2 activity, such as alopecia induced by cancer chemotherapy.
A further aspect of the invention provides a method of treatment of a human or animal body suffering from a disorder kinase is a mitogen activated protein kinase which comprises administering an effective amount of an active compound of formula (I) to the human,or animal patient.
Another aspect of the present invention, provides the use of an active compound of formula (I), in the preparation of a medicament for the treatment of malignant tumors, or for the treatment of alopecia induced by cancer chemotherapy or induced by radiation therapy. Alternatively, compounds of formula (I) can be used in the preparation of a medicament for the treatment of a disease mediated by a kinase selected from the group consisting of: abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms, c-kit, c-m t, cRaf1, CSF1R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1, IKK2, IKK3, INS-R, Integrin-linkedkinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCxcex1, PKCxcex2, PKCxcex4, PKCxcex5, PKCxcex3, PKCxcex, PKCxcexc, PKCxcex6, PLK1, Polo-like kinase, PYK2, tie1, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70. Additionally, compounds of formula (I) can be used in the preparation of a medicament for the treatment of a disease or disorder such as organ transplant rejection, tumor growth, chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia, mucocitis, plantar-palmar syndrome, restenosis, atherosclerosis, rheumatoid arthritis, angiogenesis, hepatic cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, glomerulopathy, psoriasis, diabetes mellitus, inflammation, neurodegenerative disease, macular degeneration, actinic keratosis and hyperproliferative disorders.
Another aspect of the present invention provides the use of an active compound of formula (I), in coadministration with previously known anti-tumor therapies for more effective treatment of such tumors.
Another aspect of the present invention provides the use of an active compound of formula (I) in the preparation of a medicament for the treatment of viral or eukaryotic infection.
Other aspects of the present invention related to the inhibition of mitogen activated protein kinases are discussed in more detail below.
Compounds we have synthesized as part of the present invention which are currently preferred are listed in Tables 1 and 2 below. Compounds are identified by the numbers shown in the first column; variables below in the rest of the columns are with reference to the generic structure (I). Corresponding IUPAC nomenclature are disclosed in Table 2. Since all substituents at each point of substitution are capable of independent synthesis of each other, the tables are to be read as a matrix in which any combination of substituents is within the scope of the disclosure and claims of the invention.
Standard accepted nomenclature corresponding to the Examples set forth in this specification are set forth below. In some cases nomenclature is given for one or more possible isomers.
The invention discloses 10 different points of substitution on structural formula (I). Each of these points of substitution bears a substituent whose selection and synthesis as part of this invention was independent of all other points of substitution on formula (I). Thus, each point of substitution is now further described individually.
Preferred substitutions at the R1 position include hydrogen, halogen, amide, nitro, lower alkyl, hydroxy, hydroxyalkyl, pyrimidineloweralkyl, loweralkoxycarbonyl, cyclic loweralkyl, hydroxyphenylloweralkyl, phenoxy, alkoxy and pyrazole; and R1 fused with R2 to form a fused ring selected from the group consisting of: thiazole, pyrazole, triazole, halogen-substituted diazole, acyl substituted pyrrole and pyridine. Most preferred substituents at R1 include hydrogen and methyl and R1 fused with R2for form fused thiazole or fused pyridine. The most highly preferred substitution at the R1 position is hydrogen.
Preferred substitutions at the R2 position include hydrogen, halogen, sulfate, amine, quaternary amine, amide, ester, phenyl, alkoxy, aminosulfonyl, lower alkyl sulfonyl, furanyl lower alkyl amide, pyridinyl lower alkyl amide, alkoxy-substituted phenyl lower alkyl amide, morpholino lower alkyl amide, imidazolyl lower alkyl amide, hydroxy lower alkyl amide, alkoxy lower alkyl amide, lower alkyl amide, lower alkyl sulfonamide, lower alkyl hydroxy substituted amino, nitro, halogen-substituted phenoxycarbonyl and triazole and oxazole rings, or are R2 fused with R3 to form a fused ring selected from the group consisting of: oxazole, pyrrole, and dioxolane, which fused ring is optionally substituted by lower alkyl or lower alkyl carbonyl, and which fused ring is optionally a hetero ring having nitrogen as the heteroatom and forming a quaternary ammonium salt ionically bonded with a halogen atom. Most preferred substituents at R2 include hydrogen, phenyl, 2-furanyl, 3-thiophenyl, bromo and carbethoxy.
Preferred substitutions at R3 include hydrogen, lower alkyl, hydroxy lower alkyl, halogen, phenoxy and alkoxy. Most preferred include hydrogen Hand chloro. Most highly preferred is hydrogen.
Preferred substitutions at R4 include sulfonylamino, sulfonylaminoamino, lower alkyl sulfonylamino, lower alkylsulfonyl lower alkyl, alkoxysulfonylamino, phenylcarbonylsulfonylamino, phenoxysulfonyl, hydroxy lower alkylsulfonylamino, hydroxy lower alkylsulfonylamino lower alkyl, alkyl, phenylsulfonylamino (optionally substituted by halogen-substituted lower alkyl), aminoiminosulfonylamino, alkylsulfonylaminoalkyl, pyridinyl lower alkyl sulfonylamino, benzamideazolesulfonylamino, pyridylsulfonylamino, pyrimidinylsulfonylamino, thiadiazolylsulfonylamino (optionally substituted by lower alkyl), thiazolesulfonylamino, hydroxyalkoxyalkylsulfonylamino and 4xe2x80x2-SO2NH[(CH2)2O]4CH3, or R4 fused with R5to form a fused ring selected from the group consisting of imidazole, triazole, cyclic sulfonylamino and thiaphene, where said fused ring is optionally disubstituted on the sulfur heteroatom by oxo. The most preferred substitutions include 2-pyridine sulfonylamino, 4-pyridine sulfonylamino, hydroxy n-butyl sulfonylamino, methylsulfonylaminomethylene, sulfonyldimethylamino, fused 1,2-pyrazole and sulfonylamino. In a most highly preferred embodiment, R4 is sulfonylamino or fused 1,2-pyrazole.
The preferred substitution at R5 is hydrogen.
Preferred substitutions at X include N, CH and CCH3. Most preferred is CH.
The preferred substitution at Y is N or C.
The preferred substitution at Z is N or C.
The preferred substitution at A is N or C.
The preferred substitution at D is N or C.